Immunosuppressive drugs currently in use have a variety of limitations including hepatotoxicity, nephrotoxicity, mutagenicity and other serious side effects. There is a need for new immunosuppressive drugs with reversible antiproliferative effects which are more potent on lymphocytes than on other cell types. We have recently shown that mice lacking Jak3, a protein-tyrosine kinase, are severely immunodeficient. These mice have few mature B cells and their T cells are unable to respond to mitogenic signals. In addition, human patients with defects in Jak3 signaling are severely immunocompromised having impaired B cell function and very few T cells. This suggests that JAK3, which is restricted to lymphoid cells in its expression, is an ideal target for drug-based immunosuppression. Inhibitors of Jak3 function would have immunosuppressive activity without the side effects of current agents such as Cyclosporin. To identify Jak3 inhibitors, we will develop assays, both in vitro and cellular, to define the interaction of Jak3 protein with its ligand the common gamma chain cytokine receptor. More importantly, these assays will be used to identify synthetic organic molecules that inhibit Jak3 and would be potential leads for development as immunosuppressive drugs.